Mef2c factors are required for early but not late addition of cardiomyocytes to the ventricle

TY - JOUR

T1 - Mef2c factors are required for early but not late addition of cardiomyocytes to the ventricle

AU - Kula-Alwar, Duvaraka

AU - Marber, Michael

AU - Hughes, Simon

AU - Hinits, Yaniv

N1 - Funding Information: We thank Jeroen Bakkers and Didier Stainier for transgenic lines. DK was supported by the PhD programme of the British Heart Foundation Centre of Research Excellence at King's College London. SMH is a member of MRC Scientific Staff with Programme Grant G1001029 and MR/N021231/1 support. YH was supported by British Heart Foundation Project Grant PG/14/12/30664. Funding Information: We thank Jeroen Bakkers and Didier Stainier for transgenic lines. DK was supported by the PhD programme of the British Heart Foundation Centre of Research Excellence at King’s College London. SMH is a member of MRC Scientific Staff with Programme Grant G1001029 and MR/N021231/1 support. YH was supported by British Heart Foundation Project Grant PG/14/12/30664 . Publisher Copyright: © 2020 The Authors Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/2

Y1 - 2021/2

N2 - During heart formation, the heart grows and undergoes dramatic morphogenesis to achieve efficient embryonic function. Both in fish and amniotes, much of the growth occurring after initial heart tube formation arises from second heart field (SHF)-derived progenitor cell addition to the arterial pole, allowing chamber formation. In zebrafish, this process has been extensively studied during embryonic life, but it is unclear how larval cardiac growth occurs beyond 3 days post-fertilisation (dpf). By quantifying zebrafish myocardial growth using live imaging of GFP-labelled myocardium we show that the heart grows extensively between 3 and 5 dpf. Using methods to assess cell division, cellular development timing assay and Kaede photoconversion, we demonstrate that proliferation, CM addition, and hypertrophy contribute to ventricle growth. Mechanistically, we show that reduction in Mef2c activity (mef2ca+/-;mef2cb-/-), downstream or in parallel with Nkx2.5 and upstream of Ltbp3, prevents some CM addition and differentiation, resulting in a significantly smaller ventricle by 3 dpf. After 3 dpf, however, CM addition in mef2ca+/-;mef2cb-/- mutants recovers to a normal pace, and the heart size gap between mutants and their siblings diminishes into adulthood. Thus, as in mice, there is an early time window when SHF contribution to the myocardium is particularly sensitive to loss of Mef2c activity.

AB - During heart formation, the heart grows and undergoes dramatic morphogenesis to achieve efficient embryonic function. Both in fish and amniotes, much of the growth occurring after initial heart tube formation arises from second heart field (SHF)-derived progenitor cell addition to the arterial pole, allowing chamber formation. In zebrafish, this process has been extensively studied during embryonic life, but it is unclear how larval cardiac growth occurs beyond 3 days post-fertilisation (dpf). By quantifying zebrafish myocardial growth using live imaging of GFP-labelled myocardium we show that the heart grows extensively between 3 and 5 dpf. Using methods to assess cell division, cellular development timing assay and Kaede photoconversion, we demonstrate that proliferation, CM addition, and hypertrophy contribute to ventricle growth. Mechanistically, we show that reduction in Mef2c activity (mef2ca+/-;mef2cb-/-), downstream or in parallel with Nkx2.5 and upstream of Ltbp3, prevents some CM addition and differentiation, resulting in a significantly smaller ventricle by 3 dpf. After 3 dpf, however, CM addition in mef2ca+/-;mef2cb-/- mutants recovers to a normal pace, and the heart size gap between mutants and their siblings diminishes into adulthood. Thus, as in mice, there is an early time window when SHF contribution to the myocardium is particularly sensitive to loss of Mef2c activity.

KW - zebrafish

KW - second heart field

KW - mef2c

KW - cardiomyocyte

KW - growth

UR - http://www.scopus.com/inward/record.url?scp=85097103028&partnerID=8YFLogxK

U2 - 10.1016/j.ydbio.2020.11.008

DO - 10.1016/j.ydbio.2020.11.008

M3 - Article

C2 - 33245870

SN - 0012-1606

VL - 470

SP - 95

EP - 107

JO - Developmental Biology

JF - Developmental Biology

ER -